tbuckley/cabot-search huggingface dataset:
INNV-32. COMPARING THE MONTREAL COGNITIVE ASSESSMENT (MOCA) FULL AND 5-MINUTE PROTOCOLS IN MILD COGNITIVE IMPAIRMENT SCREENING OF ADULT CNS TUMOR PATIENTS
Authors: Yeonju Kim, James Rogers, Varna Jammula, Elizabeth Vera, Alexa Christ, Heather Leeper, Alvina Acquaye, Lisa Boris, Nicole Briceno, Eric Burton, Anna Choi, Ewa Grajkowska, Edina Komlodi-Pasztor, Jason Levine, Matthew Lindsley, Nicole Lollo, Marissa Panzer, Marta Penas-Prado, Valentina Pillai, Lily Polskin, Jennifer Reyes, Kayla Roche, Matthew Smith-Cohn, Brett Theeler, Jing Wu, Mark Gilbert, Terri Armstrong
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Mild cognitive impairment (MCI) commonly occurs in primary CNS tumor patients (PCTP). Our group and others have reported on the Montreal Cognitive Assessment (MoCA) as an MCI screening tool. Several abbreviated MoCA protocols have been developed for telehealth administration in other neurological diseases, with varied literature on scoring and clinical utility. We compared MoCA Full and 5-minute scores to assess utility in neuro-oncology. METHODS 71 PCTP completed the MoCA Full (abnormal: &amp;lt; 26/30) assessing: visuospatial/executive functioning, naming, memory, attention, language, abstraction, delayed recall, and orientation. Full scores were retrospectively recoded to the Pendlebury MoCA 5-minute protocol (abnormal: &amp;lt; 10/12) assessing: memory, delayed recall, and orientation. Correlation was assessed using Pearson’s coefficient. Disagreements between tests were examined using t-test and chi-square test. RESULTS Patients were primarily White (83%), college-educated (71%) males (54%) diagnosed with glioblastoma (20%), with average age of 43 years (range: 19-75), KPS &amp;gt; 80 (57%), prior radiation treatment (78%), and imaging surveillance at time of testing (79%). MoCA Full and 5-minute mean scores were 25.3 (SD: 4.8) and 9.9 (SD: 2.3), respectively. MCI was indicated in 32% (n= 23) of patients using MoCA Full and 27% (n= 19) using MoCA 5-minute. Where the protocols disagreed, MCI was detected only by MoCA Full in 6 patients (8%), and MoCA 5-minute in 2 patients (3%). Visuospatial/executive (p= 0.025) and abstraction (p&amp;lt; 0.001) subdomain scores, unique to MoCA Full, were significantly associated with MCI detected only by the MoCA Full; other subdomains, patient characteristics, and total score were not significant. The MoCA versions were highly correlated (r= 0.90). CONCLUSION High correlation and agreement between MoCA Full and 5-minute scores in this neuro-oncology patient population highlight potential telehealth utility of the MoCA 5-minute. Future prospective assessment of the MoCA 5-minute is warranted to describe optimal scoring threshold and utility in neuro-oncology.
DNAR-08. THE ROLE OF SMARCAL1 AS A SYNTHETIC LETHAL VULNERABILITY IN ATRX-DEFICIENT GLIOMAS
Authors: Matthew Waitkus, Heng Liu, Alexandrea Brown, Laura Strickland, Taher Khambati, Casey Fraley, Bill Diplas, Stephen Keir, David Ashley
Journal: Neuro-Oncology (2022)

Abstract Mechanisms to maintain telomere length over successive cell divisions are a requirement for cancer cell immortalization. Although many cancers maintain telomere length through the activation of telomerase, ~10-15% of human cancers use telomerase-independent mechanisms of telomere maintenance, termed Alternative Lengthening of Telomeres (ALT). In gliomas, the ALT phenotype is associated with loss-of-function mutations in the ATRX gene in IDH-mutant astrocytomas, adult and pediatric glioblastomas (GBM), high-grade astrocytomas with piloid features, and pleomorphic xanthoastrocytomas. In adult GBM, we previously identified a relatively rare subset of ALT-positive ATRX wildtype tumors that harbored loss-of-function mutations in the SMARCAL1 gene, and we found that loss of SMARCAL1 activity plays a causative role in the onset of ALT in these tumors. SMARCAL1 is an annealing helicase that localizes to sites of DNA damage and replication stress and catalyzes the reversal of stalled replication forks. To better understand the relationship between ATRX mutations, SMARCAL1 activity, and the ALT phenotype, we investigated the localization and function of SMARCAL1 in ALT-positive glioma cells and xenografts with native ATRX deficiency. We found that SMARCAL1 localizes to ALT-associated PML bodies in astrocytoma cell lines with concurrent ATRX and IDH1 mutations (derived from grade 3 and 4 tumors). Our data show that inducible suppression of SMARCAL1 via doxycycline-induced RNAi leads to increased DNA double-strand breaks, increased abundance of extrachromosomal telomeric repeats (c-circles), and increased sensitivity to irinotecan, a topoisomerase I inhibitor. In an orthotopic mouse model, SMARCAL1 depletion exhibited a chemosensitizing effect in combination with irinotecan against a patient-derived xenograft (astrocytoma, IDH-mutant Grade 4). Based on these data, we hypothesize that SMARCAL1 activity is critical for resolving ALT-associated replication stress in ATRX-deficient malignant gliomas. We therefore propose that SMARCAL1 functions as a synthetic lethal vulnerability in ATRX-deficient ALT-positive gliomas and that SMARCAL1 inhibition is a viable therapeutic strategy in these tumors.
NCMP-08. THE EFFECTIVENESS OF ANTISEIZURE MEDICATION TRIPLETHERAPY IN GLIOMA PATIENTS WITH REFRACTORY EPILEPSY: A MULTICENTER OBSERVATIONAL COHORT STUDY
Authors: Pim van der Meer, Linda Dirven, Marta Fiocco, Maaike Vos, Mathilde Kouwenhoven, Martin van den Bent, Martin Taphoorn, Johan Koekkoek
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND About 10% of glioma patients with epilepsy need antiseizure medication (ASM) tripletherapy due to refractory epilepsy. This study aimed to determine whether levetiracetam combined with valproic acid and clobazam (LEV+VPA+CLB), a commonly prescribed tripletherapy, has favorable effectiveness compared to other tripletherapy combinations in glioma patients. METHODS In this multicenter retrospective observational cohort study, the primary outcome was to estimate the cumulative incidence of treatment failure for any reason, from initiation of ASM tripletherapy. Secondary outcomes included cumulative incidences of: 1) treatment failure due to uncontrolled seizures; 2) treatment failure due to adverse effects; and 3) recurrent seizure. Maximum duration of follow-up was 36 months. RESULTS Out of n=1435 patients in the original cohort, n=90 patients received ASM tripletherapy after second-line ASM treatment failure due to uncontrolled seizures. LEV+VPA+CLB was prescribed to 48% (43/90) and other ASM tripletherapy to 52% (47/90) patients. The cumulative incidence of treatment failure for any reason of LEV+VPA+CLB did not significantly differ from other tripletherapy (12 months: 47% [95%CI, 31-62%] versus 42% [95%CI, 27-56%], p=0.892). No statistical significant differences for treatment failure due to uncontrolled seizures (12 months: 12% [95%CI, 4-25%] versus 18% [95%CI, 8-30%], p=0.445), due to adverse effects (12 months: 22% [95%CI, 11-36%] versus 15% [95%CI, 7-27%], p=0.446), or recurrent seizure (1 month: 65% [95%CI, 48-78%] versus 63% [95%CI, 47-75%], p=0.911) were found. CONCLUSIONS LEV+VPA+CLB showed equivalent effectiveness compared to other ASM tripletherapy combinations in glioma patients.
NCOG-24. TIME TO FIRST RECURRENCE AND SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA
Authors: Peter Pan, Adela Joanta-Gomez, Carlen Yuen, Laura Donovan, Aya Haggiagi, Mary Welch, Fabio Iwamoto, Andrew Lassman
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Time to recurrence is a source of considerable anxiety in glioblastoma. Assuming survival to a certain timepoint without tumor progression, how do odds/outcomes change relative to initial starting conditions? Is there a single timepoint with highest risk of tumor progression, after which "the longer you go, the longer you go"? METHODS Newly-diagnosed glioblastomas were retrospectively reviewed (n=209). Pre-2012 diagnoses (n=2) &amp; IDH-mutants excluded (n=8). Median PFS/OS and remaining time to mPFS were calculated for sub-populations without disease progression (POD) at 0, 3, 6, 8, 12, and 24 months post-surgery. RESULTS 199 IDH-wildtype glioblastomas identified -- 40% women, median age 63 years (range 26-91), 43% gross-total resection, 65% MGMT unmethylated, 65% upfront RT 60Gy (23% 40Gy) -- mPFS 8 months / mOS 19 months. Patients without POD within 3 months had mOS 20 months. Outcomes progressively improve at later timepoints-- mPFS 10/13/20/39 months and mOS 23/27/39/65 months, for patients without POD at 6/8/12/24 months post-surgery respectively. Patients without POD at 24 months comprised 10% of original cohort (n=20; 8 deaths). As a surrogate for risk of tumor progression, remaining time to mPFS was calculated (taken as difference between timepoint in question, and mPFS for the population of patients without POD up to that timepoint) and followed a J-shape curve -- 8 months (at 0 months post-surgery), 4 months (for patients without POD at 6 months post-surgery), 7-8 months (for patients without POD at 10-14 months post-surgery), to 13 and 15 months (for patients without POD at 18 and 24 months post-surgery, respectively). DISCUSSION Sub-populations without early progression appear to have improved survival relative to baseline, which has implications for clinical trials without internal controls. Nevertheless, highest risk for tumor progression seems to be at 6 months post-surgery, after which it appears "the longer you go, the longer you go."
TMIC-75. TUMOR ENDOTHELIAL CELL-DERIVED ASPORIN DIFFERENTIALLY REGULATES GLIOBLASTOMA GROWTH
Authors: Sree Deepthi Muthukrishnan, Amy Pham, Alvaro Alvarado, Riki Kawaguchi, Harley Kornblum
Journal: Neuro-Oncology (2022)

Abstract Gliomas are the most prevalent and malignant brain tumors. A major histopathological feature that distinguishes the high-grade (IV) glioblastoma (GBM) from slow-growing low-grade (II and III) glioma is microvascular hyperproliferation. Although gliomas are highly vascularized tumors, anti-angiogenic therapies have failed to prevent recurrence and significantly improve patient survival. To determine if tumor endothelial cells (TEC) display molecular heterogeneity, we performed bulk RNA-sequencing on cultured CD31+ TEC from low-grade (II/III), and high-grade (IV, primary and recurrent) gliomas. Low- and high-grade TEC exhibited significant molecular heterogeneity, with increased enrichment of extracellular matrix and cell cycle-related gene sets in low-grade and enrichment of cytokine and immune response-related gene sets in high-grade TEC. We also found significant functional differences in proliferation capacity, and resistance to anti-angiogenic therapies between low-and high-grade TEC. Co-transplantation of low-grade TEC with tumor cells significantly inhibited GBM growth and enhanced survival, whereas high-grade TEC promoted growth of tumors in orthotopic xenografts in vivo. Differential gene expression analysis revealed several proteoglycans distinctly expressed by low-grade TEC. Of the highly enriched molecules in low-grade TEC, Asporin (ASPN), a small leucine-rich repeat proteoglycan (SLRP) significantly inhibited growth and proliferation of IDH1-wt GBM cells but did not affect IDH1-mutant tumor cells. Co-transplantation of TEC-lacking ASPN with IDH1-wt GBM partially rescued the growth-inhibitory effect of low-grade TEC on tumor growth and reduced survival. Ongoing experiments are aimed at determining the molecular mechanism underlying the growth-inhibitory effects of TEC-derived Asporin on glioma.
EXTH-86. BH3 PROFILING IDENTIFIES ONC201/TIC10 AS A PROMISING PARTNER OF ABT-263 IN MEDULLOBLASTOMA IN VITRO
Authors: Antonia Spilz, Annika Hajosch, Felix Seyfried, Aurelia Peraud, Varun V Prabhu, Joshua E Allen, Mike-Andrew Westhoff, Markus Siegelin, Christian Rainer Wirtz, Georg Karpel-Massler
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Medulloblastoma represents one of the most common brain tumors in children. In this study, we identified by BH3 profiling that ONC201/TIC10 sensitizes for Bcl-xL/Bcl-2 inhibition in medulloblastoma and performed a preclinical testing of a combined treatment with ONC201/TIC10 and the Bcl-xL/Bcl-2 inhibitor ABT-263. METHODS BH3 profiling was performed to examine ONC201/TIC10-mediated dependencies on anti-apoptotic Bcl-2 family proteins. The combination treatment with ONC201/TIC10 and ABT-263 was tested in different medulloblastoma cells using MTT assays. Isobolograms were calculated to characterize the drug-drug interaction. Tumor spheroid and chorioallantoic membrane assays were used to examine the effects of the combination therapy in a 3D setting. Annexin V/PI staining and flowcytometry were used to detect pro-apoptotic effects. Western blot analyses and knockdown experiments with siRNA were performed for molecular analysis. Extracellular flux analyses served at examining effects on the tumor cell metabolism. RESULTS BH3 profiling showed that ONC201/TIC10 sensitizes medulloblastoma cells to Bcl-xL/Bcl-2 inhibition. In line with this finding, combined treatment with ONC201/TIC10 and ABT-263 led to a predominantly synergistic inhibitory effect on the cell viability of established (D425, D458, DAOY, HD-MB03), primary cultured (PC322) and stem-like (SC322) medulloblastoma cells in 2D and 3D models. The response towards the combination therapy was independent of baseline c-myc expression. On the molecular level, treatment with ONC201/TIC10 led to a dose-dependent decrease of Mcl-1. Moreover, the combination caused enhanced cleavage of caspases 9 and 3. On the metabolic level, the combination therapy led to a reduction in both, oxidative phosphorylation and the glycolytic rate and a reduced expression of respiratory chain proteins. CONCLUSION Combined treatment with ONC201/TIC10 and ABT-263 had a predominantly synergistic inhibitory effect on the cell viability of medulloblastoma cells. This effect was associated with downregulation of Mcl-1. Moreover, the combination treatment resulted in a metabolic reprogramming which likely creates a state of energy deprivation.
EXTH-20. IDENTIFICATION OF EX VIVO THERAPEUTIC VULNERABILITIES IN DIFFUSE GLIOMAS USING A FUNCTIONAL GENOMICS APPROACH
Authors: Wan-Hsin Lin, James Smadbeck, Michael Barrett, Ryan Feathers, Sadeghian Dorsay, Sarah Johnson, Giannoula Karagouga, Faye Harris, Stephen Murphy, Alfredo Quiñones-Hinojosa, Sani Kizilbash, Terry Burns, Kurt Jaeckle, Maciej Mrugala, Bernard Bendok, Diogo Moniz-Garcia, Shannon Fortin-Ensign, Steven Rosenfeld, Cristiane Ida, Mark Jentoft, Marcela Salomao, Lin Yang, Angela Emanuel, Janet Schaefer-Klein, Aaron Mansfield, Mitesh Borad, John Cheville, George Vasmatzis, Panos Anastasiadis
Journal: Neuro-Oncology (2022)

Abstract Diffuse gliomas are aggressive brain tumors that lack effective therapies. Despite advances in the molecular characterization of gliomas, targeted treatments have failed to improve patient outcomes to date. Here, we employed a functional genomics approach to rapidly identify therapeutic vulnerabilities and provide a strategy to individualize patient treatment. Our process combined comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensional ex vivo models (mcancers) for drug screening to assess response to therapeutic agents targeting specific molecular alterations. A total of 32 cases, including 5 oligodendrogliomas (1 primary and 4 recurrent), 5 astrocytomas (1 primary and 4 recurrent), and 22 glioblastomas (5 primary and 17 recurrent), were included in the study. Immunohistochemistry and integrated genomics confirmed that mcancers maintain key molecular alterations, including mutations, chromosomal rearrangements and focal amplifications, cellularity, and heterogeneity, faithfully recapitulating the original tumor. A total of 119 single drugs and 183 combinations were tested, including a panel of 26-brain penetrant targeted agents (18 single drugs and 8 combinations) that was curated to target common glioma oncogenic pathways and was tested across all cases. A strong correlation was observed between therapeutic vulnerabilities of glioma mcancers to targeted agents (EGFR, MET, PDGFR, HDAC inhibitors, etc.) and clinical experience. Single agent activity of panel compounds in the ex vivo setting was generally poor, with only 35% mCancers exhibiting &amp;gt; 70% growth inhibition at Cmax. In contrast, combination strategies, especially ones including epigenetic drugs, were significantly more effective (affecting 22 out of 32 mCancers), underscoring the molecular complexity of gliomas and the need for clinical trials testing combination treatments. Our data identified a number of novel combination treatments with significant efficacy across glioma subtypes and molecular profiles, suggesting that our functional genomics pipeline can guide treatment selection and inform clinical trial enrollment for gliomas.
TMIC-77. SINGLE-CELL CHARACTERIZATION OF HUMAN GBM REVEALS REGIONAL DIFFERENCES IN TUMOR-INFILTRATING LEUKOCYTE ACTIVATION
Authors: Philip Schmassmann, Julien Roux, Steffen Dettling, Sabrina Hogan, Tala Shekarian, Tomas A Martins, Marie-Françoise Ritz, Sylvia Herter, Gregor Hutter
Journal: Neuro-Oncology (2022)

Abstract Clinical trials of systemic T cell checkpoint blockade in GBM patients showed only disappointing results. This may be attributed in part to the immunosuppressive components of the GBM immune tumor microenvironment (iTME). Therefore, major efforts have been undertaken to describe the GBM iTME on a single cell level. However, human data on the composition of the iTME in different tumor regions (contrast enhancing tumor center versus peripheral infiltration zone) remain scarce. Here, we performed high-depth single-cell RNA sequencing (scRNAseq) on patient-matched biopsies from the tumor center and the peripheral infiltration zone of five primary GBM patients. Additionally, peripheral blood mononuclear cells (PBMC) of the same patients were included in the scRNAseq analysis to explore the transcriptional changes occurring during tumor infiltration of circulating immune cells. Through analysis of &amp;gt; 45’000 cells, we revealed a distinct regional transcriptional profile of microglia (MG) and monocyte-derived macrophages (MdM), a non-reactive/exhausted MG subcluster in the GBM iTME and an impaired interferon-response signature in the peripheral cytotoxic cell compartment. Comparing CD8+ T-cells from the tumor periphery to PBMC-derived CD8+ T-cells of the same patient revealed a CX3CR1+ CD8+ T-cell population with effector memory phenotype which is enriched in the PBMC but lacking in the tumor periphery. Peripheral CD8+ T-cells were mainly composed of tissue-resident memory CD8+ T-cells with exhausted effector functions. Our analysis provides a large-scale dissection of GBM-associated cell types complemented by patient-matched PBMCs, serving as a high dimensional reference map of the human GBM iTME.
CTNI-42. GENOME-WIDE DNA METHYLATION PATTERNS IN VERTU: A RANDOMIZED PHASE II TRIAL OF VELIPARIB, RADIOTHERAPY AND TEMOZOLOMIDE IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Hao-Wen Sim, Zarnie Lwin, Elizabeth Barnes, Kerrie McDonald, Eng-Siew Koh, Mark Rosenthal, Matthew Foote, Michael Back, Helen Wheeler, Michael Buckland, Kyle Walsh, Lauren Fisher, Robyn Leonard, Merryn Hall, David Ashley, Sonia Yip, John Simes, Erik Sulman, Mustafa Khasraw
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND VERTU was a randomized phase II trial evaluating veliparib, a brain-penetrant PARP inhibitor, combined with radiotherapy and temozolomide, for patients with newly diagnosed MGMT-unmethylated glioblastoma. As part of planned correlative work after study completion, we assessed genome-wide DNA methylation patterns to predict methylation class, glioblastoma subtype and MGMT status. METHODS Patients were randomized 2:1 to experimental (60Gy/30 fractions with veliparib 200mg bid, then temozolomide 150-200mg/m2 D1-5 + veliparib 40mg bid D1-7 Q28D for 6 cycles) versus standard arm (60Gy/30 fractions with temozolomide 75mg/m2 daily, then temozolomide 150-200mg/m2 D1-5 Q28D for 6 cycles). The primary objective to improve 6-month progression-free survival (PFS-6m) was not met (doi: 10.1093/neuonc/noab111). Methylation data were generated using the Illumina Infinium Methylation EPIC bead chip array. Tumor tissues were categorized using the Heidelberg methylation-based classifier. RESULTS Methylation data were successfully generated for 98/125 patients (poor quality DNA [n = 12], no consent [n = 11], insufficient tissue [n = 4]). Those with classifier scores below 0.5 (n = 25), tumor microenvironment only (n = 6) and rediagnosis as pleomorphic xanthoastrocytoma (n = 1) were excluded, leaving n = 66. Methylation classes were GBM RTK II (n = 23, PFS-6m 43% [95%CI 23-62]), RTK I (n = 20, PFS-6m 50% [95%CI 27-69]), MES (n = 20, PFS-6m 40% [95%CI 19-60]), MID (n = 2) and G34 (n = 1). Glioblastoma subtypes were mesenchymal (n = 28, PFS-6m 50% [95%CI 30-66]), proneural (n = 24, PFS-6m 50% [95%CI 29-68]) and classical (n = 14, PFS-6m 36% [95%CI 13-59]). MGMT status were unmethylated (n = 58, PFS-6m 48% [95%CI 35-60]) and methylated (n = 8, PFS-6m 38% [95%CI 9-67]). There was no evidence of interaction between treatment arm and methylation class (excluding GBM MID and G34, P = 0.45), glioblastoma subtype (P = 0.68) or MGMT status (P = 0.52). CONCLUSIONS Genome-wide DNA methylation patterns in VERTU identified a spectrum of methylation-defined subgroups, reflecting tumoral heterogeneity. This may have utility for future clinical trials and practice. The effect of veliparib in VERTU appeared to be consistent across subgroups. ACTRN12615000407594.
MODL-17. SEGMENTATION OF PRE AND POST-TREATMENT GLIOMA TISSUE TYPES INCLUDING RESECTION CAVITIES
Authors: Nathan White, Saif Baig, Igor Vidic, George Mastorakos, Robert Smith, Anders Dale, Carrie McDonald, Thomas Beaumont, Tyler Seibert, Srinivas Peddi, Jona Hattangadi-Gluth, Nikdokht Farid, Santosh Kesari, Jeffrey Rudie
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Measuring gliomas is a time-intensive process with significant inter-rater variability in post-surgical residual tumor and resection cavities. This likely contributes to the delayed assessment of progression and in-field recurrences from radiation. Automated segmentation of pre and post-treatment gliomas could reduce inter-rater variability and increase workflow efficiency for routine longitudinal radiographic assessment and treatment planning. We evaluated whether a 3D neural network is comparable to expert assessment of pre and post-treatment diffuse gliomas tissue types and resection cavities. METHODS A retrospective cohort of 647 MRIs of patients with diffuse gliomas (average 55.1 years, 45% female, 396 pre-treatment and 251 post-treatment, median 237 days post-surgery) from The Cancer Imaging Archive were stratified by operation status and tumor grade and randomly split into training (536) and testing (111) samples. T1, T1-post-contrast, T2, and FLAIR images were registered, skull-stripped, and interpolated to 1x1x1. Four classes — edema/infiltrative/post-treatment changes (ED), enhancing tissue (ET), necrotic core (NCR), and resection cavities (RC) — were manually segmented by an expert neuroradiologist. Using these segmentations and the four input image modalities, a nnU-Net, a state-of-the-art 3D U-Net convolutional neural network, was trained to predict segmentations of the four classes. RESULTS Segmentation performance in the test set for the ED, ET, and RC classes was at the level of inter-rater reliability with median Dice scores ranging from 0.85 to 1 and relative volume errors ranging from -0.05 to 0.02. There was a near-perfect correlation between manually segmented and predicted total lesion volumes (r2 values ranging from 0.95 to 0.98 among classes). CONCLUSIONS Accurate, automated volumetric quantification of diffuse glioma tissue volumes may improve response assessment in clinical trials and reduce provider burden and errors in measurement.